Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1

评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗

• 批准号: 10300442
• 负责人: Andrew McGuire
• 金额: $ 11.73万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300442
• 关键词: Adoptive Transfer; Affinity; Amino Acids; Animal Model; Animals; Anti-Idiotypic Antibodies; Antibodies; Antibody Binding Sites; Antibody Formation; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Binding Sites; Biological Assay; CD4 Positive T Lymphocytes; Cattle; Cell Separation; Cloning; Collaborations; Data; Development; Engineering; Epitope Mapping; Epitopes; Failure; Gene Targeting; Genes; Genetic; Glycoproteins; Goals; Growth; HIV Infections; HIV-1; HIV-1 vaccine; Human; Immune response; Immunization; Immunodominant Epitopes; In Vitro; Individual; Infection; Infection prevention; Knock-in; Knock-in Mouse; Light; Llama; Longevity; Modeling; Monoclonal Antibodies; Mus; Mutation; Peptides; Peripheral Blood Mononuclear Cell; Process; Reaction; Reagent; Recombinant Antibody; Recombinants; Research; Sampling; Sequence Homology; Site; Specificity; Structure of germinal center of lymph node; Surface; T cell response; T-Lymphocyte; Testing; Transgenic Mice; Vaccination; Vaccines; Viral; Virion; Work; antigen binding; base; design; experimental study; humanized mouse; immunogenic; immunogenicity; improved; in vivo; insight; knockin animal; mouse model; neutralizing antibody; novel; novel vaccines; progenitor; recruit; response; tool; vaccine candidate

Project Summary/Abstract Broadly neutralizing antibodies (bNAbs) that bind to the HIV-1 Envelope glycoprotein (Env) are expected to be an important component of the immune response elicited by an effective HIV-1 vaccine. However, efforts to elicit bNAbs through vaccination with recombinant Env have not yet been successful. VRC01-class antibodies are among the broadest and most potent bNAbs that have been isolated from infected individuals, and their elicitation would be an ideal goal of a vaccine. VRC01-class antibodies have been isolated from multiple donors, and they all interact with Env in a nearly identical manner; are derived from the same antibody heavy chain gene, VH1-2*02; and have an unusually short third complimentary determining region (CDRL3) on the light chain. During the course of infection, VRC01-class antibodies acquired a number of mutations in their antibody genes that allow them recognize and neutralize diverse HIV-1 viral isolates. Using sequence homology, one can predict the sequence of the B-cell receptor (BCR) on the naive B cell that gave rise to each VRC01-class antibody. Previous work from our group and others has demonstrated that these inferred-germline versions of VRC01-class antibodies fail to recognize diverse recombinant Envs. Thus, conventional Env immunogens are likely ineffective at binding to and activating naive B cells that can give rise to VRC01-class antibodies. The structural similarity and shared genetics of VRC01-class antibodies have led to the proposal that immunogens designed to specifically to engage VRC01-class precursor B cells could, at the very least, start the process of VRC01-class antibody production. Indeed we, and others, have designed Env-based immunogens that can activate B cells expressing VRC01-class precursor BCRs in vitro and in vivo. However, these immunogens also present off-target, potentially immunodominant epitopes that could ultimately frustrate the development of VRC01-class antibodies in competitive germinal center reactions. As an alternative to Env-derived immunogens, we have produced and isolated anti-idiotypic antibodies that are highly specific for the antigen binding site of VRC01-class precursor BCRs. Importantly, because they are non-Env derived, they lack the off-target epitopes present on other germline-targeting immunogens. Our overarching hypothesis is that if used as a vaccine prime, anti-idiotypic antibodies can selectively seek out and expand rare VRC01-class B cells, such that the expanded pool will have a selective advantage over other B cells that respond to off-target epitopes following a boost with germline-targeting Env. This hypothesis will be tested in transgenic mouse models as part of this HIVRAD application, in collaboration with Drs. Stamatatos and Nussenzweig. The focus of this project is to evaluate the ability of these novel immunogens to seek out rare VRC01-class precursor B cells from human PBMC samples and from mice expressing a diverse human-derived BCR repertoire, and to engineer multivalent aiMAb derivatives to improve immunogenicity.

项目摘要/摘要 与HIV-1包膜糖蛋白（ENV）结合的广泛中和抗体（BNAB）预计 成为有效HIV-1疫苗引起的免疫反应的重要组成部分。但是，努力 通过重组ENV疫苗接种引起BNABS尚未成功。 VRC01级抗体 是从感染者及其 诱导将是疫苗的理想目标。 VRC01级抗体已从多个供体中分离出来， 他们都以几乎相同的方式与Env互动。来自相同的抗体重链基因， VH1-2*02;并在轻链上具有异常短的第三次免费确定区域（CDRL3）。 在感染过程中，VRC01级抗体在其抗体中获得了许多突变 允许它们识别并中和不同的HIV-1病毒分离株的基因。使用序列同源性，可以 在幼稚的B细胞上预测B细胞受体（BCR）的序列，从而导致每种VRC01级 抗体。我们小组和其他人的先前工作表明，这些推断的网格线版本 VRC01级抗体无法识别各种重组ENV。因此，常规的ENV免疫原是 可能无效地结合并激活可引起VRC01级抗体的幼稚B细胞。 VRC01级抗体的结构相似性和共享遗传学导致了以下提议： 旨在专门参与VRC01级前体B细胞的免疫原子至少可以启动 VRC01级抗体产生的过程。确实，我们和其他人已经设计了基于ENV的免疫原子 这可以激活B细胞在体外和体内表达VRC01级前体BCR。但是，这些 免疫原还表现出脱靶的，潜在的免疫主导表现，最终可能会使人沮丧 竞争性生发中心反应中VRC01级抗体的开发。 作为环境衍生的免疫原子的替代方法，我们已经产生并分离了抗二动型抗体 对于VRC01级前体BCR的抗原结合位点高度特异。重要的是，因为他们是 他们衍生出的非ENV缺乏其他靶向种系免疫原子上存在的脱靶表位。我们的 总体假设是，如果用作疫苗素，抗IDiotypic抗体可以选择性地寻找和 扩展稀有的VRC01级B细胞，使扩展的池将比其他B细胞具有选择性优势 在推动生殖线靶向Env的提升之后，这对脱靶表位做出了反应。该假设将进行检验 在转基因鼠标模型中，作为此Hivrad应用程序的一部分，与DRS合作。 Stamatatos和 Nussenzweig。该项目的重点是评估这些新颖的免疫原子寻求罕见的能力 来自人类PBMC样品的VRC01级前体B细胞和表达人类衍生多样的小鼠的小鼠 BCR曲目，以及设计多价AIMAB衍生物以改善免疫原性。